Nonlinear protein binding and enzyme heterogeneity: effects on hepatic drug removal

The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity.     

Alteration of Sertoli cell differentiation in the presence of carcinoma in situ in human testes

PURPOSE: We investigated Sertoli cells in testicular biopsies with carcinoma in situ (CIS) in respect to cytokeratin expression to elucidate the status of Sertoli cell differentiation adjacent to CIS in human testes. Cytokeratin 18 intermediate filaments indicate a state of undifferentiation usually observed in Sertoli cells of prepubertal testes. MATERIALS AND METHODS: 29 testicular biopsies presenting CIS were investigated by means of immunohistochemistry, using a polyclonal antibody against placental-alkaline phosphatase to detect CIS cells and a monoclonal antibody against human cytokeratin 18 to show expression of cytokeratin 18 intermediate filaments in Sertoli cells. RESULTS: All tubules bearing CIS showed positive cytokeratin expression of Sertoli cells if tubules were devoid of normal germ cells. However, a total of 13 specimen revealed CIS cells together with normal germ cells. In the presence of CIS cells together with round or elongated spermatids, adjacent Sertoli cells did not express cytokeratin immunoreactivity. In the case of combined presence of CIS and spermatogonia and primary spermatocytes, Sertoli cells could be found either immunopositive or immunonegative, and were positive in tubules with CIS and spermatogonia only. CONCLUSIONS: Sertoli cells associated with CIS cells undergo a process of dedifferentiation, seen by the re-expression of cytokeratin intermediate filaments. We suggest that this dedifferentiation results in a loss of Sertoli cell function and leads to a cessation of spermatogenic activity.     

The role of perspective in the accessibility of goals during reading.

An implicit assumption of several causal reasoning models is that readers adopt the goals of a narrative's protagonist during text comprehension. In apparent violation of this assumption, readers participating in Experiment 1 of the present study drew inferences relevant to a protagonist's goal even when that goal was already satisfied from the perspective of the protagonist. In Experiments 2 and 3, participants were explicitly asked to view the text situation from the point of view of the protagonist. In this case, the goals of the reader and the protagonist should be the same. In these experiments, participants focused on the goals of the protagonist only when those goals had not been satisfied from the perspective of the protagonist. These results are discussed in terms of reader- and character-based perspectives and in terms of text characteristics that cue perspective taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clinical risk factors determining recurrence in Crohn''s disease

Absorbable and nonabsorbable buried sutures were studied in primary cleft lip repair. Group 1 (N = 56) consisted of patients repaired with buried nonabsorbable material (monofilament nylon). Group 2 (N = 47) consisted of patients repaired with absorbable materials (polyglyconate, polydioxanone). All patients were monitored for 12 months. There were stitch abscesses in Group 1 (14%). There were no abscesses in Group 2. This difference was significant (p = 0.007). Abscesses were located in the suture line with no identifiable distribution. There was no significant difference in the cosmetic appearance of the scars in Groups 1 and 2. These results support the view that absorbable sutures are preferable to nonabsorbable sutures for primary cleft lip repair.     

Shear horizontal wave propagation in periodically layeredcomposites

The transverse resonance approach to guided wave analysis is applied to shear horizontal (SH) wave propagation in periodically layered composites. It is found for SH waves that at high values of the guided wavevector β, the wave energy is trapped in the slower of the two media and propagates accordingly at the slower wavespeed. At low values of β, however, the modes demonstrate a clustering behavior, indicative of the underlying Floquet wave structure. The number of modes in a cluster is observed to correlate with the number of unit cells in the layered plate. New physical insights into the behavior of these systems are obtained by analyzing the partial waves of the guided SH modes in terms of Floquet waves. We show that the fast and slow shear waves in the periodically layered composite play an analogous role to the longitudinal and shear partial waves comprising Lamb waves in a homogeneous plate     

Enterococcal bacteremia in a medical center

BACKGROUND: The enterococci have become important nosocomial pathogens. They can cause multiple site infections and enterococcal bacteremia becomes more frequently associated with a high mortality rate. Previous studies of enterococcal bacteremia showed a variety of results. To establish the significance and importance of enterococci as nosocomial pathogens in this hospital, to characterize their clinical pictures and to search for the risk factors for mortality, this retrospective study was performed. METHODS: There were 208 cases of enterococcal bacteremia which occurred from 1988 to 1992. Twenty-seven cases had no medical charts, dismissing possibility of evaluation. Finally, 181 cases of enterococcal bacteremia were analysed. RESULTS: One hundred and eighteen episodes were nosocomial infections. Polymicrobial bacteremia occurred in 68.5% of the patients and the most common co-isolate was Pseudomonas aeruginosa. Those patients (78.5%) with underlying diseases and malignancies were the most common underlying problems. The portal of entry could be found in 69.6 percent of patients, with the gastrointestinal tract the most common sources. Antimicrobial susceptibility testing showed high gentamicin resistance rate (89.5%), and ampicillin still had about 80 percent sensitivity rate. The group who received specific antibiotic therapy for enterococcus showed lower mortality (36.4% versus 47.6%). Only one case had infective endocarditis. Forty-nine patients suffered from septic shock, the cause of 30 deaths. Totally 75 patients died during hospitalization. Besides sepsis, another major cause of death was their underlying diseases itself. CONCLUSIONS: Enterococci have no doubt become important nosocomial pathogens and enterococcal bacteremia were associated with high mortality, especially in elderly patients with underlying diseases such as malignancy or diabetes. When clinically dealing with sepsis from the gastrointestinal or biliary tract, especially when previous cephalosporins therapy showed no response, the possibility of enterococcal bacteremia should always be considered.     

Nonpigmented fixed drug eruption from pseudoephedrine

The biotransformation of oxazepam by Bifidobacterium bifidum was studied. The major metabolite was purified by chromatographic methods and found to be desmethyldiazepam using NMR, IR and other physicochemical data.